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Abstract Digital health technologies (DHTs) have the potential to modernize drug development and clinical trial operations by remotely, passively, and continuously collecting ecologically valid evidence that is meaningful to patients’ lived experiences. Such evidence holds potential for all drug development stakeholders, including regulatory agencies, as it will help create a stronger evidentiary link between approval of new therapeutics and the ultimate aim of improving patient lives. However, only a very small number of novel digital measures have matured from exploratory usage into regulatory qualification or efficacy endpoints. This shows that despite the clear potential, actually gaining regulatory agreement that a new measure is both fit-for-purpose and delivers value remains a serious challenge. One of the key stumbling blocks for developers has been the requirement to demonstrate that a digital measure is meaningful to patients. This viewpoint aims to examine the co-evolution of regulatory guidance in the United States (U.S.) and best practice for integration of DHTs into the development of clinical outcome assessments. Contextualizing guidance on meaningfulness within the larger shift towards a patient-centric drug development approach, this paper reviews the U.S. Food and Drug Administration (FDA) guidance and existing literature surrounding the development of meaningful digital measures and patient engagement, including the recent examples of rejections by the FDA that further emphasize patient-centricity in digital measures. Finally, this paper highlights remaining hurdles and provides insights into the established frameworks for development and adoption of digital measures in clinical research.

The relationship between tumor microenvironments (TMEs) of regional lymph node metastases (LNMs) and primary tumors in head and neck squamous cell carcinoma (HNSCC) remains unclear. This study compared tumor-infiltrating lymphocytes (TILs) and the immune phenotype (IP), characterized by spatial TIL distribution, between primary tumors and LNMs. Twenty-one HNSCC patients with regional LNM who received immune checkpoint inhibitors (ICIs) were included. A paired comparative analysis of TIL densities and IP between primary tumors and LNMs revealed no significant difference or correlation between TIL densities in primary tumors and LNMs. Their IPs were discordant in 12 patients (57.1%). Patients with high intratumoral TIL exhibited longer progression-free survival (PFS) than those with low intratumoral TIL in both primary tumors (median, 5.2 vs. 1.3 months, p = 0.003) and LNMs (median, 30.2 vs. 1.3 months, p = 0.012). Patients with inflamed IP exhibited longer PFS than those with non-inflamed IP in both primary tumors (median, 4.5 vs. 1.3 months, p = 0.043) and LNMs (median, 4.1 vs. 1.3 months, p = 0.037). Given the lack of correlation in TIL densities, the discrepancies in IP, and the predictive value of both TMEs, evaluating the TMEs of both primary tumors and LNMs may be beneficial for the precise use of ICIs in HNSCC. There was a significant discordance between the TME of primary tumors and LNMs, with implications in survival outcomes. Therefore, evaluating the TME of both the primary tumor and LNM could be beneficial for the precise use of ICIs in HNSCC.

Summary: Background: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes. Methods: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype. Findings: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4–3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9–3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002). Interpretation: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response. Funding: This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program.

Abstract Background De-implementation requires understanding and targeting multilevel determinants of low-value care. The objective of this study was to identify multilevel determinants of imaging for prostate cancer (PCa) and asymptomatic microhematuria (AMH), two common urologic conditions that have contributed substantially to the annual spending on unnecessary imaging in the US. Methods We used a convergent mixed-methods approach involving survey and interview data. Using a survey, we asked 33 clinicians (55% response-rate) to indicate their imaging approach to 8 clinical vignettes designed to elicit responses that would demonstrate guideline-concordant/discordant imaging practices for patients with PCa or AMH. A subset of survey respondents (N = 7) participated in semi-structured interviews guided by a combination of two frameworks that offered a comprehensive understanding of multilevel determinants. We analyzed the interviews using a directed content analysis approach and identified subthemes to better understand the differences and similarities in the imaging determinants across two clinical conditions. Results Survey results showed that the majority of clinicians chose guideline-concordant imaging behaviors for PCa; guideline-concordant imaging intentions were more varied for AMH. Interview results informed what influenced imaging decisions and provided additional context to the varying intentions for AMH. Five subthemes touching on multiple levels were identified from the interviews: National Guidelines, Supporting Evidence and Information Exchange, Organization of the Imaging Pathways, Patients’ Clinical and Other Risk Factors, and Clinicians’ Beliefs and Experiences Regarding Imaging. Imaging decisions for both PCa and AMH were often driven by national guidelines from major professional societies. However, when clinicians felt guidelines were inadequate, they reported that their decision-making was influenced by their knowledge of recent scientific evidence, past clinical experiences, and the anticipated benefits of imaging (or not imaging) to both the patient and the clinician. In particular, clinicians referred to patients’ anxiety and uncertainty or patients’ clinical factors. For AMH patients, clinicians additionally expressed concerns regarding legal liability risk. Conclusion Our study identified comprehensive multilevel determinants of imaging to inform development of de-implementation interventions to reduce low-value imaging, which we found useful for identifying determinants of de-implementation. De-implementation interventions should be tailored to address the contextual determinants that are specific to each clinical condition.

BackgroundWhile online portals may be helpful to engage patients in shared decision-making at the time of cancer screening, because of known disparities in patient portal use, sole reliance on portals to support cancer screening decision-making could exacerbate well-known disparities in this health care area. Innovative approaches are needed to engage patients in health care decision-making and to support equitable shared decision-making. ObjectiveWe assessed the acceptability of text messages to engage sociodemographically diverse individuals in colorectal cancer (CRC) screening decisions and support shared decision-making in practice. MethodsWe developed a brief text message program offering educational information consisting of components of shared decision-making regarding CRC screening (eg, for whom screening is recommended, screening test options, and pros/cons of options). The program and postprogram survey were offered to members of an online panel. The outcome of interest was program acceptability measured by observed program engagement, participant-reported acceptability, and willingness to use similar programs (behavioral intent). We evaluated acceptability among historically marginalized categories of people defined by income, literacy, and race. ResultsOf the 289 participants, 115 reported having a low income, 146 were Black/African American, and 102 had less than extreme confidence in their health literacy. With one exception, we found equal or greater acceptability, regardless of measure, within each of the marginalized categories of people compared to their counterparts. The exception was that participants reporting an income below US $50,000 were less likely to engage with sufficient content of the program to learn that there was a choice among different CRC screening tests (difference –10.4%, 95% CI –20.1 to –0.8). Of note, Black/African American participants reported being more likely to sign up to receive text messages from their doctor’s office compared to white participants (difference 18.7%, 95% CI 7.0-30.3). ConclusionsStudy findings demonstrate general acceptance of text messages to inform and support CRC screening shared decision-making.

Abstract Objectives Ground-glass opacity (GGO) on computed tomography is associated with prognosis in early-stage non-small cell lung cancer (NSCLC) patients. However, the stratification of the prognostic value of GGO is controversial. We aimed to evaluate clinicopathologic characteristics of early-stage NSCLC based on the consolidation-to-tumor ratio (CTR), conduct multi-pronged analysis, and stratify prognosis accordingly. Methods We retrospectively investigated 944 patients with clinical stage IA NSCLC, who underwent curative-intent lung resection between August 2018 and January 2020. The CTR was measured and used to categorize patients into six groups (1, 0%; 2, 0–25%; 3, 25–50%; 4, 50–75%; 5, 75–100%; and 6, 100%). Results Pathologic nodal upstaging was found in 1.8% (group 4), 9.0% (group 5), and 17.4% (group 6), respectively. The proportion of patients with a high grade of tumor-infiltrating lymphocytes tended to decrease as the CTR increased. In a subtype analysis of patients with adenocarcinoma, all of the patients with predominant micro-papillary patterns were in the CTR > 50% groups, and most of the patients with predominant solid patterns were in group 6 (47/50, 94%). The multivariate analysis demonstrated that CTR 75–100% (hazard ratio [HR], 3.85; 95% confidence interval [CI], 1.58–9.36) and CTR 100% (HR, 5.58; 95% CI, 2.45–12.72) were independent prognostic factors for DFS, regardless of tumor size. Conclusion We demonstrated that the CTR could provide various noninvasive clinicopathological information. A CTR of more than 75% is the factor associated with a poor prognosis and should be considered when making therapeutic plans for patients with early-stage NSCLC.

The World Health Organization Classification of Tumors of the Central Nervous System recently incorporated histological features, immunophenotypes, and molecular characteristics to improve the accuracy of glioblastoma (GBM) diagnosis. FGFR3::TACC3 (F3T3) fusion has been identified as an oncogenic driver in IDH-wildtype GBMs. Recent studies have demonstrated the potential of using FGFR inhibitors in clinical trials and TACC3-targeting agents in preclinical models for GBM treatment. However, there is limited information on the clinicopathological and genetic features of IDH-wildtype GBMs with F3T3 fusion. The aim of this study was to comprehensively investigate the clinical manifestations, histological features, and mutational profiles of F3T3-positive GBMs. Between September 2017 and February 2023, 25 consecutive cases (5.0%) of F3T3-positive GBM were extracted from 504 cases of IDH-wildtype GBM. Clinicopathological information and targeted sequencing results obtained from 25 primary and 4 recurrent F3T3-positive GBMs were evaluated and compared with those from F3T3-negative GBMs. The provisional grades determined by histology only were distributed as follows: 4 (26/29; 89.7%), 3 (2/29; 6.9%), and 2 (1/29; 3.4%). Grade 2–3 tumors were ultimately diagnosed as grade 4 GBMs based on the identification of the TERT promoter mutation and the combined gain of chromosome 7 and loss of chromosome 10 (7+/10−). F3T3-positive GBMs predominantly affected women (2.6 females per male). The mean age of patients with an F3T3-positive GBM at initial diagnosis was 62 years. F3T3-positive GBMs occurred more frequently in the cortical locations compared to F3T3-negative GBMs. Imaging studies revealed that more than one-third (12/29; 41.4%) of F3T3-positive GBMs displayed a circumscribed tumor border. Seven of the seventeen patients (41.2%) whose follow-up periods exceeded 20 months died of the disease. Histologically, F3T3-positive GBMs more frequently showed curvilinear capillary proliferation, palisading nuclei, and calcification compared to F3T3-negative GBMs. Molecularly, the most common alterations observed in F3T3-positive GBMs were TERT promoter mutations and 7+/10−, whereas amplifications of EGFR, PDGFRA, and KIT were not detected at all. Other genetic alterations included CDKN2A/B deletion, PTEN mutation, TP53 mutation, CDK4 amplification, and MDM2 amplification. Our observations suggest that F3T3-positive GBM is a distinct molecular subgroup of the IDH-wildtype GBM. Both clinicians and pathologists should consider this rare entity in the differential diagnosis of diffuse astrocytic glioma to make an accurate diagnosis and to ensure appropriate therapeutic management.

Non-fluent variant primary progressive aphasia (nfvPPA), a subtype of frontotemporal lobar dementia syndrome, has been proven to have various pathological diagnoses. A 63-year-old woman and 71-year-old man separately visited our clinic for language dysfunction. Both patients showed non-fluent speech. The female patient showed personality change accompanied by language dysfunction, while the male patient had parkinsonian symptoms such as bradykinesia and cogwheel rigidity. Both patients were clinically diagnosed with nfvPPA. Several years after the first visit, the patients died, and a brain autopsy was performed. On postmortem examination, the female patient was pathologically diagnosed with Pick’s disease, while the male patient was diagnosed with progressive supranuclear palsy. Our report suggests that nfvPPA patients might show distinct clinical features depending on underlying pathologies.

BackgroundExtensive literature support telehealth as a supplement or adjunct to in-person care for the management of chronic conditions such as congestive heart failure (CHF) and type 2 diabetes mellitus (T2DM). Evidence is needed to support the use of telehealth as an equivalent and equitable replacement for in-person care and to assess potential adverse effects. ObjectiveWe conducted a systematic review to address the following question: among adults, what is the effect of synchronous telehealth (real-time response among individuals via phone or phone and video) compared with in-person care (or compared with phone, if synchronous video care) for chronic management of CHF, chronic obstructive pulmonary disease, and T2DM on key disease-specific clinical outcomes and health care use? MethodsWe followed systematic review methodologies and searched two databases (MEDLINE and Embase). We included randomized or quasi-experimental studies that evaluated the effect of synchronously delivered telehealth for relevant chronic conditions that occurred over ≥2 encounters and in which some or all in-person care was supplanted by care delivered via phone or video. We assessed the bias using the Cochrane Effective Practice and Organization of Care risk of bias (ROB) tool and the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation. We described the findings narratively and did not conduct meta-analysis owing to the small number of studies and the conceptual heterogeneity of the identified interventions. ResultsWe identified 8662 studies, and 129 (1.49%) were reviewed at the full-text stage. In total, 3.9% (5/129) of the articles were retained for data extraction, all of which (5/5, 100%) were randomized controlled trials. The CHF study (1/5, 20%) was found to have high ROB and randomized patients (n=210) to receive quarterly automated asynchronous web-based review and follow-up of telemetry data versus synchronous personal follow-up (in-person vs phone-based) for 1 year. A 3-way comparison across study arms found no significant differences in clinical outcomes. Overall, 80% (4/5) of the studies (n=466) evaluated synchronous care for patients with T2DM (ROB was judged to be low for 2, 50% of studies and high for 2, 50% of studies). In total, 20% (1/5) of the studies were adequately powered to assess the difference in glycosylated hemoglobin level between groups; however, no significant difference was found. Intervention design varied greatly from remote monitoring of blood glucose combined with video versus in-person visits to an endocrinology clinic to a brief, 3-week remote intervention to stabilize uncontrolled diabetes. No articles were identified for chronic obstructive pulmonary disease. ConclusionsThis review found few studies with a variety of designs and interventions that used telehealth as a replacement for in-person care. Future research should consider including observational studies and studies on additional highly prevalent chronic diseases.

Abstract Background Clinical practice guidelines recommend active surveillance as the preferred treatment option for low-risk prostate cancer, but only a minority of eligible men receive active surveillance, and practice variation is substantial. The aim of this study is to describe barriers to urologists’ recommendation of active surveillance in low-risk prostate cancer and explore variation of barriers by setting. Methods We conducted semi-structured interviews among 22 practicing urologists, evenly distributed between academic and community practice. We coded barriers to active surveillance according to a conceptual model of determinants of treatment quality to identify potential opportunities for intervention. Results Community and academic urologists were generally in agreement on factors influencing active surveillance. Urologists perceived patient-level factors to have the greatest influence on recommendations, particularly tumor pathology, patient age, and judgements about the patient’s ability to adhere to follow-up protocols. They also noted cross-cutting clinical barriers, including concerns about the adequacy of biopsy samples, inconsistent protocols to guide active surveillance, and side effects of biopsy procedures. Urologists had differing opinions on the impact of environmental factors, such as financial disincentives and fear of litigation. Conclusions Despite national and international recommendations, both academic and community urologists note a variety of barriers to implementing active surveillance in low risk prostate cancer. These barriers will need to be specifically addressed in efforts to help urologists offer active surveillance more consistently.

Abstract Amphiregulin (AREG) is a transmembrane glycoprotein recently implicated in kidney fibrosis. Previously, we reported that the AREG-targeting Self-Assembled-Micelle inhibitory RNA (SAMiRNA-AREG) alleviated fibrosis by stably silencing the AREG gene, and reduced the side effects of conventional siRNA treatment of pulmonary fibrosis. However, the therapeutic effect of SAMiRNA-AREG in renal fibrosis has not been studied until now. We used two animal models of renal fibrosis generated by a unilateral ureteral obstruction (UUO) and an adenine diet (AD) to investigate whether SAMiRNA-AREG inhibited renal fibrosis. To investigate the delivery of SAMiRNA-AREG to the kidney, Cy5-labeled SAMiRNA-AREG was injected into UUO- and AD-induced renal fibrosis models. In both kidney disease models, SAMiRNA-AREG was delivered primarily to the damaged kidney. We also confirmed the protective effect of SAMiRNA-AREG in renal fibrosis models. SAMiRNA-AREG markedly decreased the UUO- and AD-induced AREG mRNA expression. Furthermore, the mRNA expression of fibrosis markers, including α-smooth muscle actin, fibronectin, α1(I) collagen, and α1(III) collagen in the UUO and AD-induced kidneys, was diminished in the SAMiRNA-AREG-treated mice. The transcription of inflammatory markers (tumor necrosis factor-α and monocyte chemoattractant protein-1) and adhesion markers (vascular cell adhesion molecule 1 and intercellular adhesion molecule 1) was attenuated. The hematoxylin and eosin, Masson’s trichrome, and immunohistochemical staining results showed that SAMiRNA-AREG decreased renal fibrosis, AREG expression, and epidermal growth factor receptor (EGFR) phosphorylation in the UUO- and AD-induced models. Moreover, we studied the effects of SAMiRNA-AREG in response to TGF-β1 in mouse and human proximal tubule cells, and mouse fibroblasts. TGF-β1-induced extracellular matrix production and myofibroblast differentiation were attenuated by SAMiRNA-AREG. Finally, we confirmed that upregulated AREG in the UUO or AD models was mainly localized in the distal tubules. In conclusion, SAMiRNA-AREG represents a novel siRNA therapeutic for renal fibrosis by suppressing EGFR signals.

The microcystic, elongated, and fragmented (MELF) pattern is a unique myometrial invasion pattern occasionally found at the invasive front of endometrial endometrioid carcinoma (EEC). Herein, we report an uncommon case of usual-type endocervical adenocarcinoma (UEA) with a MELF pattern. We comprehensively analyzed its clinicopathological and molecular features, which has not been previously documented. A 67-year-old woman presented with a cervical mass and underwent radical hysterectomy. Histologically, the MELF pattern of UEA was almost identical to that of EEC. Tumor glands exhibited a microcystic appearance or elongated structures with compression forming a slit-like lumen. The tumor glands were irregularly fragmented into small clusters or single cells. Cells lining the tumor glands possessed conspicuous eosinophilic cytoplasm with squamoid or flattened endothelium-like appearance. These glands or cells were accompanied by a prominent fibromyxoid stromal reaction. Lymphovascular invasion was occasionally observed. Immunostaining revealed diffuse and strong cytokeratin 7 expression and block p16 positivity in both conventional and MELF components. However, the MELF component displayed a very low Ki-67 proliferation index compared to that of the conventional component, which showed markedly increased Ki-67 expression. Targeted sequencing analysis revealed that the MELF component harbored pathogenic mutations in ARID1A, KRAS, and PTEN, identical to those detected in the conventional component. In summary, the morphological features of the MELF pattern in UEA were similar to those in EEC. We found significant differences in Ki-67 expression status between conventional and MELF components, but the mutational profiles were identical. Our findings should be confirmed in larger cohorts of patients with UEA showing a MELF pattern.

Abstract Background Implementation science has focused mainly on the initial uptake and use of evidence-based practices (EBPs), with less attention to sustainment—i.e., continuous use of these practices, as intended, over time in ongoing operations, often involving adaptation to dynamic contexts. Declining EBP use following implementation is well-documented yet poorly understood. Using theories, models, and frameworks (TMFs) to conceptualize sustainment could advance understanding. We consolidated knowledge from published reviews of sustainment studies to identify TMFs with the potential to conceptualize sustainment, evaluate past uses of TMFs in sustainment studies, and assess the TMFs’ potential contribution to developing sustainment strategies. Methods We drew upon reviews of sustainment studies published within the past 10 years, evaluated the frequency with which included articles used a TMF for conceptualizing sustainment, and evaluated the relevance of TMFs to sustainment research using the Theory, Model, and Framework Comparison and Selection Tool (T-CaST). Specifically, we examined whether the TMFs were familiar to researchers, hypothesized relationships among constructs, provided a face-valid explanation of relationships, and included sustainment as an outcome. Findings Nine sustainment reviews referenced 648 studies; these studies cited 76 unique TMFs. Only 28 TMFs were used in more than one study. Of the 19 TMFs that met the criteria for T-CaST analysis, six TMFs explicitly included sustainment as the outcome of interest, 12 offered face-valid explanations of proposed conceptual relationships, and six identified mechanisms underlying relationships between included constructs and sustainment. Only 11 TMFs performed adequately with respect to all these criteria. Conclusions We identified 76 TMFs that have been used in sustainment studies. Of these, most were only used once, contributing to a fractured understanding of sustainment. Improved reporting and use of TMFs may improve understanding of this critical topic. Of the more consistently used TMFs, few proposed face-valid relationships between included constructs and sustainment, limiting their ability to advance our understanding and identify potential sustainment strategies. Future research is needed to explore the TMFs that we identified as potentially relevant, as well as TMFs not identified in our study that nonetheless have the potential to advance our understanding of sustainment and identification of strategies for sustaining EBP use.

Abstract Introduction: The US National Institutes of Health (NIH) established the Clinical and Translational Science Award (CTSA) program in response to the challenges of translating biomedical and behavioral interventions from discovery to real-world use. To address the challenge of translating evidence-based interventions (EBIs) into practice, the field of implementation science has emerged as a distinct discipline. With the distinction between EBI effectiveness research and implementation research comes differences in study design and methodology, shifting focus from clinical outcomes to the systems that support adoption and delivery of EBIs with fidelity. Methods: Implementation research designs share many of the foundational elements and assumptions of efficacy/effectiveness research. Designs and methods that are currently applied in implementation research include experimental, quasi-experimental, observational, hybrid effectiveness–implementation, simulation modeling, and configurational comparative methods. Results: Examples of specific research designs and methods illustrate their use in implementation science. We propose that the CTSA program takes advantage of the momentum of the field's capacity building in three ways: 1) integrate state-of-the-science implementation methods and designs into its existing body of research; 2) position itself at the forefront of advancing the science of implementation science by collaborating with other NIH institutes that share the goal of advancing implementation science; and 3) provide adequate training in implementation science. Conclusions: As implementation methodologies mature, both implementation science and the CTSA program would greatly benefit from cross-fertilizing expertise and shared infrastructures that aim to advance healthcare in the USA and around the world.

Background Tumor mutational burden (TMB) measurement is limited by low tumor purity of samples, which can influence prediction of the immunotherapy response, particularly when using whole-exome sequencing-based TMB (wTMB). This issue could be overcome by targeted panel sequencing-based TMB (pTMB) with higher depth of coverage, which remains unexplored.Methods We comprehensively reanalyzed four public datasets of immune checkpoint inhibitor (ICI)-treated cohorts (adopting pTMB or wTMB) to test each biomarker’s predictive ability for low purity samples (cut-off: 30%). For validation, paired genomic profiling with the same tumor specimens was performed to directly compare wTMB and pTMB in patients with breast cancer (paired-BRCA, n=165) and ICI-treated patients with advanced non-small-cell lung cancer (paired-NSCLC, n=156).Results Low tumor purity was common (range 30%–45%) in real-world samples from ICI-treated patients. In the survival analyzes of public cohorts, wTMB could not predict the clinical benefit of immunotherapy when tumor purity was low (log-rank p=0.874), whereas pTMB could effectively stratify the survival outcome (log-rank p=0.020). In the paired-BRCA and paired-NSCLC cohorts, pTMB was less affected by tumor purity, with significantly more somatic variants identified at low allele frequency (p

Summary: Exome and transcriptome analyses of clinically homogeneous early-stage never-smoker female patients with lung adenocarcinoma were performed to understand tumor-T cell interactions and immune escape points. Using our novel gene panels of eight functional categories in the cancer-immunity cycle, three distinct subgroups were identified in this immune checkpoint blockade-refractory cohort by defective gene expression in two major domains, i.e., type I interferon production/signaling pathway and antigen-presenting machinery. Our approach could play a critical role in understanding immune evasion mechanisms, developing a method for effective selection of rare immune checkpoint blockade responders, and finding new treatment strategies.

Abstract Background Although prostate cancer is the most common cancer among veterans receiving care in the Veterans Health Administration (VA), more needs to be done to understand and improve survivorship care for this large population. This study, funded by VA Health Services Research & Development (HSR&D), seeks to address the need to improve patient-centered survivorship care for veterans with prostate cancer. Methods/Design This is a two-armed randomized controlled trial (RCT) with a target enrollment of up to 325 prostate cancer survivors per study arm (total anticipated n = 600). Patients will be recruited from four VA sites. Patient eligibility criteria include age range of 40–80 years, one to ten years post-treatment, and currently experiencing prostate cancer symptom burden. We will compare the “Building Your New Normal” program, a personally-tailored automated telephone symptom management intervention for improving symptom self-management to usual care enhanced with a non-tailored newsletter about symptom management. Primary outcomes include changes in symptom burden, bother, and health services utilization at five and 12 months after enrollment. Secondary outcomes include long-term psychosocial outcomes (e.g. subjective health, perceived cancer control). We will use multivariable regression analysis to evaluate the impact of the intervention on primary and secondary outcomes. We will conduct a process evaluation to understand the effective intervention components and explore possibilities for broader implementation and dissemination. Discussion Our central hypothesis is that intervention group participants will have improved and more confident symptom self-management and prostate cancer quality of life following the intervention and that these outcomes will translate to more efficient use of health services. The study results will provide much needed information about how to optimize the quality of care, and life, of veteran prostate cancer survivors. Trial registration ClinicalTrials.gov ID NCT01900561 ; Registered on 22 July 2013.

Charcot–Marie–Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 Korean CMT families and excluded 344 families with a PMP22 duplication. We further analyzed the 799 remaining families to find their GNB4 mutations using whole-exome sequencing (WES). We identified two mutations (p.Gly77Arg and p.Lys89Glu) in three families, among which a heterozygous p.Gly77Arg mutation was novel. In addition, a significant uncertain variant (p.Thr177Asn) was observed in one family. The frequency of the GNB4 mutation in the Korean population is 0.38% in PMP22 duplication-negative families. All three families showed de novo mutation. Electrophysiological findings regarding the p.Lys89Glu mutation showed that the motor nerve conduction velocity (MNCV) of the median nerve was markedly reduced, indicating demyelinating neuropathy, and sural nerve biopsy revealed severe loss of myelinated axons with onion bulb formation. Lower extremity Magnetic Resonance Imaging (MRI) demonstrated relatively more severe intramuscular fat infiltrations in demyelinating type (p.Lys89Glu mutation) patients compared to intermediate type (p.Gly77Arg mutation) patients. The anterolateral and superficial posterior compartment muscles of the distal calf were preferentially affected in demyelinating type patients. Therefore, it seems that the investigated GNB4 mutations do cause not only the known intermediate type but also demyelinating-type neuropathy. We first presented three Korean families with GNB4 mutations and found phenotypic heterogeneities of both intermediate and demyelinating neuropathy. We suggest that those findings are useful for the differential diagnosis of CMT patients with unknown GNB4 variants.

Background We reviewed a series of 188 resected pulmonary mucinous adenocarcinomas (MAs) to clarify the prognostic significance of lepidic and non-lepidic patterns. Methods Non-lepidic patterns were divided into bland, non-distorted acini with uncertain invasiveness (pattern 1), unequivocal invasion into stroma (pattern 2), or invasion into alveolar spaces (pattern 3). Results The mean proportion of invasive patterns (patterns 2 and 3) was lowest in small (≤ 3 cm) tumors, and gradually increased in intermediate (> 3 cm and ≤ 7 cm) and large (> 7 cm) tumors (8.4%, 34.3%, and 50.1%, respectively). Adjusted T (aT) stage, as determined by the size of invasive patterns, was positively correlated with adverse histologic and clinical features including older age, male sex, and ever smokers. aTis tumors, which were exclusively composed of lepidic pattern (n = 9), or a mixture of lepidic and pattern 1 (n = 40) without any invasive patterns, showed 100% disease- free survival (DFS). The aT1mi tumors, with minimal (≤ 5 mm) invasive patterns (n = 63), showed a 95.2% 5-year DFS, with recurrences (n = 2) limited to tumors greater than 3 cm in total size (n = 23). Both T and aT stage were significantly associated with DFS; however, survival within the separate T-stage subgroups was stratified according to the aT stage, most notably in the intermediatestage subgroups. In multivariate analysis, the size of invasive patterns (p = .020), pleural invasion (p < .001), and vascular invasion (p = .048) were independent predictors of recurrence, whereas total size failed to achieve statistical significance (p = .121). Conclusions This study provides a rationale for histologic risk stratification in pulmonary MA based on the extent of invasive growth patterns with refined criteria for invasion.

Ovarian gynandroblastoma (GAB) is an extremely rare sex cord-stromal tumor showing morphological evidence of both female (granulosa cell tumor) and male (Sertoli–Leydig cell tumor (SLCT)) components. Almost all GAB cases have been reported in children, adolescents, or women of reproductive age, and most of them typically have adult granulosa cell tumors as the female component. In contrast, GAB with a juvenile granulosa cell tumor (JGCT) component is a very rare condition; to the best of our knowledge, only one case of GAB with JGCT in a postmenopausal woman has been reported. In this report, we present an extremely rare case of ovarian GAB with JGCT in an elderly patient. A 65-year-old woman presented with an abdominal mass. Abdominopelvic magnetic resonance imaging revealed a large multiseptated cystic mass measuring 20 cm. No peritoneal seeding, lymph node enlargement, or hematogenous metastasis was identified. Laboratory test showed a slight elevation of serum CA 125 level (37.1 U/mL). Based on the preoperative clinical impression of ovarian cancer, she underwent a total hysterectomy with bilateral salpingo-oophorectomy. Grossly, the ovarian mass had a smooth and glistening surface without excrescences. The cut sections showed yellow-to-tan solid areas with foci of necrosis, myxoid degeneration, and hemorrhage, as well as multilocular cystic cavities filled with serosanguinous fluid. Histologically, the female component was characterized by JGCT displaying nodular growth patterns with follicle-like structures of various shapes and sizes. Most of the microcysts contained eosinophilic or basophilic secretions. The JGCT cells had indistinct cell borders, an abundant eosinophilic cytoplasm, and round-to-oval hyperchromatic nuclei with many mitotic figures. The SLCT component consisted predominantly of intermediately differentiated Sertoli cells forming lobulated solid nodules. They were arranged in cords, solid tubules, or nests, and possessed oval-to-spindle-shaped darkly stained nuclei and scant cytoplasm. In several foci, well-formed Sertoli cell tubules were loosely aggregated within areas of moderately differentiated SLCT. In summary, we described GAB in a postmenopausal woman with JGCT and SLCT as the female and male components, respectively. This is the second case of GAB with JGCT occurring in an elderly patient. Our findings can help pathologists and clinicians make accurate histological diagnoses of GAB with a JGCT component and plan an adequate treatment strategy for this rare tumor.

Most malignant tumors originate from epithelial tissues in which tight junctions mediate cell−cell interactions. Tight junction proteins, especially claudin-3 (CLDN3), are overexpressed in various cancers. Claudin-3 is exposed externally during tumorigenesis making it a potential biomarker and therapeutic target. However, the development of antibodies against specific CLDN proteins is difficult, because CLDNs are four-transmembrane domain proteins with high homology among CLDN family members and species. Here, we developed a human IgG1 monoclonal antibody (h4G3) against CLDN3 through scFv phage display using CLDN3-overexpressing stable cells and CLDN3-embedded lipoparticles as antigens. The h4G3 recognized the native conformation of human and mouse CLDN3 without cross-reactivity to other CLDNs. The binding kinetics of h4G3 demonstrated a sub-nanomolar affinity for CLDN3 expressed on the cell surface. The h4G3 showed antibody-dependent cellular cytotoxicity (ADCC) according to CLDN3 expression levels in various cancer cells by the activation of FcγRIIIa (CD16a). The biodistribution of h4G3 was analyzed by intravenous injection of fluorescence-conjugated h4G3 which showed that it localized to the tumor site in xenograft mice bearing CLDN3-expressing tumors. These results indicate that h4G3 recognizes CLDN3 specifically, suggesting its value for cancer diagnosis, antibody-drug conjugates, and potentially as a chimeric antigen receptor (CAR) for CLDN3-expressing pan-carcinoma.